A study of the genes of individuals from just eight families suffering a rare genetic syndrome, has given Professor Stephen Robertson hope that treatments may one day be developed for patients with brain injury. The people in the study had brains with grey matter in the centre of their brains, in addition to the outside. And the genes responsible have been identified. The research has led to an understanding that the seat of the abnormality is how stem cells in the middle of the brain regulate their production of neurons. Once this regulation is understood further, it is hoped treatments might be developed to encourage these cells to respond, and help heal a damaged brain.

Transcript

Robyn Williams: Sometimes though nature goes wrong. It's experimenting. Stephen Robertson found this when examining the brains of children. The grey matter, usually on the outside, was somehow in the middle. And this is just the kind of failure in nature that can lead to bright ideas, like using stem cells to repair brains. But, starting at the beginning, Stephen Robertson:

Stephen Robertson: So we worked backwards from a rare genetic syndrome that we realised was out there and had been apparent in individual cases over the last few decades, and we gathered these individuals together and aggregated it and gave this condition a name and then sought to find its genetic basis using very high throughput DNA sequencing technologies.

And having found the two genes which we could convincingly demonstrate had defects within them that underlay the syndrome, we showed that these two genes must have some key role in how the brain puts itself together. That's because when you did MRI scans on these children with this condition, it demonstrated abnormalities of how the brain is layered, that there is grey matter sitting in the centre of the brain and it just shouldn't be there. Grey matter is meant to form the outer layer of your brain, that sort of worm-like, convoluted surface that we associate with the brain, and this grey matter was stuck in the middle. Not all of it of course, these children still had grey matter on the outside of the brain but they had this extra layer. And that said to us, well, there's something in the way these neurons are being born that failed to deliver the message to them to not only differentiate, proliferate and then migrate to their position during neurogenesis, but it also interfered with the connectivity of their brain is well. And so inherent in that we thought we could find two key genes which were important in brain development.

Robyn Williams: Going back to the children themselves, well, what are they like, what's different about them?

Stephen Robertson: They are peculiar. I think we'll recognise the ability to perhaps walk down the street and spot an individual, say with Down syndrome, because they have a characteristic look to them. These children are the same, perhaps not that same gestalt which we would all be comfortable with spotting, identifying and putting a name to, but certainly they look different.

They have abnormalities elsewhere, not just in the brain. They have problems with their limbs, abnormalities in the structures of the heart, the respiratory tract and their kidneys. But primarily the thing which seemed to be the most clear to us was this novel biology, this brain phenotype which you could see on these MRI scans.

So these children had varying degrees of intellectual disability. Surprisingly none of them had any seizure activity, that would be something that we would have expected actually with this sort of biology, so that was a surprise. And they also have some limitations in terms of how they get around because of these abnormalities.

Robyn Williams: Many of them, these children?

Stephen Robertson: No, this thing is vanishingly rare. So my colleagues in western Europe and the UK, we've amassed eight families with this condition so far. But now that we've just begun to publish our findings there might be a dawning realisation on physicians all around the world that in fact perhaps a patient or two in their clinic has this condition.

Robyn Williams: It's been a mystery that they couldn't quite put a finger on and it has kind of lingered.

Stephen Robertson: That's right. We clinical geneticists have many mysteries in our clinics. I'm one myself. I spend 30% of my time seeing families and children with disorders and trying to diagnose them, and I am singularly unsuccessful in a surprisingly large slab of them. But others, it's just a case of me being able to put two and two together and connect the dots.

Robyn Williams: Well, now here you are on the front cover of a magazine in New Zealand, 'Gene Hunter: How a Kiwi came home from Oxford to lead world-class research and unlock human brain mystery'. That's getting a lot of attention and a lot of hope presumably from people who might be affected.

Stephen Robertson: Yes, the leverage from this I think perhaps goes broader though in that here we are understanding that the seat of this abnormality is how stem cells in the middle of the brain regulate their production of neurones. And that's something that speaks to brain injury, that as infants especially we have the ability for these stem cells to step forward and fill the breach. If we should be so unfortunate as to damage brain cells early on in life, we have these stem cells resident in the middle of our brain.

And so we've understood one facet of stem cell regulation here. And once you begin to be able to put a name to the regulators, you have identified pathways and you have identified drug targets potentially. So the blue-sky hope here is that by understanding this biology maybe we can regulate or interfere with the regulation of those stem cells, in the context of brain injury.

Robyn Williams: Not putting stem cells in from outside.

Stephen Robertson: That's right, the hope here is that these are endogenous.

Robyn Williams: Because there has always been a problem, if I may say, that if you do that with stem cells from outside there is a problem with tumours.

Stephen Robertson: That's precisely right. I think that is a bogey that hangs over the whole stem cell field. We need to be able to regulate these stem cells very closely if we are going to administer them as you suggest. But no, this population is endogenous. It's quite large in the newborn infant brain, but it has all but vanished by about 18 months. There are scattered stem cells in our ageing adult brains, and there is much hope pinned onto being able to harness them. But I think purely by numbers I have some optimism in my heart that we can perhaps harness this population of cells in the context of injury.

Robyn Williams: So what next really?

Stephen Robertson: Well, I think we need to understand the pathway a whole lot better here. The human brain I think is likely to have employed some new tricks over the last few million years of evolution to bring about such a huge increase in the size of our brain, and that is evident just on an anatomical basis. And so what we've found here perhaps is just a foothold in our understanding by studying this syndrome. Sure, we modelled it in mice in our study. We showed that a player of…a well-known pathway is now a player in brain development.

But what we don't understand are the intermediate steps. We don't know who's holding hands with who all the way through that chain of signalling, and we need to get a grip on that if we are going to begin to even pretend that we can intervene therapeutically to nudge this pathway in the context, as I say, of brain injury around the time of birth.

Robyn Williams: It sounds very exciting.

Stephen Robertson: I'm excited, you can probably glean. I'm an optimist as well, and I think a lot of science talks in terms of these blue skies, these horizons, and sometimes things over the horizon. I think it's important to have that vision. I think we shouldn't shy away from the fact that we can have our dreams. But I wouldn't want to sit here today and say we are on the cusp of delivering. But boy oh boy, we're trying.

Robyn Williams: It sums it up really, doesn't it; a Science Show on daring dreams and lots of trying. Stephen Robertson's work was published in Nature Genetics. He is Professor of Paediatrics at the University of Otago in New Zealand, and, as you heard, part of a worldwide team.

Guests

Stephen Robertson

Professor of Paediatric GeneticsUniversity of OtagoDunedin New Zealand